Calcium functions as an intracellular mediator of a variety of physiological activities in cells. These activities include gene regulation, DNA synthesis, cell cycle regulation, signal transduction, release of neurotransmitters in the brain, and the breakdown of glycogen for muscle contraction. These effects are initiated when extracellular signals trigger the release of calcium either from the extracellular space or the endoplasmic reticulum into the cytosol. There, calcium binds to a variety of calcium-binding proteins that further mediate the signal by activating other molecules leading to a particular physiological effect.
Calcium-binding proteins (CBP) are a super family of proteins related by the presence of a calcium-binding motif referred to as the "EF-hand" domain. This domain is characterized by a 12 amino acid loop flanked by two alpha-helices oriented at approximately 90.degree. to one another (Celio, M. R. et al. (1996) Guidebook to Calcium-binding Proteins, Oxford University Press, Oxford, UK, pp. 15-20). Most CBPs have multiple EF-hand motifs for binding calcium, and more than 250 such CBPs have been described.
Calmodulin (CaM) is the most widely distributed and the most common mediator of calcium effects (Celio set al., supra pp. 34-40). CaM appears to be the primary sensor of Ca.sup.+2 changes in eukaryotic cells. The binding of Ca.sup.+2 to CaM induces marked conformational changes in the protein that permits it to interact with, and regulate the activity of well over 100 different proteins. CaM interactions are involved in a multitude of cellular processes including, but not limited to, gene regulation, DNA synthesis, cell cycle progression, mitosis, cytokinesis, cytoskeletal organization, muscle contraction, signal transduction, ion homeostasis, exocytosis, and metabolic regulation.
CaM contains two pairs of EF-hand domains, located in the N and C-terminal halves of the molecule, and connected by a flexible central helix. Binding of Ca.sup.+2 to the EF-hand domains of CaM induces a conformational change in the protein. In the presence of a target peptide, a further conformational change results in the flexible central helix being partially unwound and wrapped around the target peptide. In this manner, CaM interacts with a wide variety of target proteins. Several post-translational modifications of CaM including acylation of the amino terminus, and phosphorylation of various serine and threonine residues have been reported.
The regulation of CBPs has implications for the control of a variety of disorders. Calcineurin, a CaM-regulated protein phosphatase, is a target for inhibition by the immunosuppressive agents cyclosporin and FK506. This indicates the importance of calcineuron, and hence of CaM, in the immune response and immune disorders (Schwaninger M. et al. (1993) J. Biol Chem. 268:23111-15). The level of CaM is increased several-fold in tumors and tumor-derived cell lines for various types of cancer (Rasmussen, C. D. and Means, A. R. Trends in Neuroscience (1989) 12: 433-38).
The discovery of a new disease associated calmodulin protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer and immune and reproductive disorders.